Multiple indications for everolimus after liver transplantation in current clinical practice

Table 1 Characteristics of recipients, donors, surgery and post-transplant evolution in 74 patients receiving everolimus n (%)

Recipient	Mean age (yr)	55.5 ± 9 r (25-69)
	Patients > 65 yr	10 (13.5)
	Male/female	55 (74.3)/19 (25.7)
	Diagnosis
	HCC with cirrhosis	35 (47.2)
	Alcoholic cirrhosis	18 (24.3)
	HCV cirrhosis	16 (21.6)
	Cholostatic cirrhosis	3 (4.1)
	Liver insufficiency	2 (2.8)
	HCV - HBV	40 (54)-3 (4)
	ETOH	38 (51.4)
	HIV	4 (5.4)
	Child-Pugh A/B/C (%)	35-30-35
	UNOS (home/Hosp/ICU (%)	90.5-6.8-2.7
	Pre-LT associated disease
	Renal insufficiency	11 (14.9)
	Diabetes mellitus	18 (24.3)
	Arterial hypertension	14 (18.9)
	Cardiopathy	3 (4.1%)
	Previous surgery	15 (20.3)
Donor	Mean age (yr)	48 ± 19 r (14-81)
	Patients > 70 yr	14 (19)
	Male/female (%)	49 (66)/25 (34)
	Graft steatosis > 20%	11 (15)
	Death (CET, CVA, Other) (%)	43-43-14
Surgery	E-E/E-E + Kehr/C-Y (%)	84-8-8
	Previous portal thrombosis	10 (13.6)
	Median RBC units	4 (r: 0-40)
	Cold ischaemia time (min)	378 ± 97
Post-transplant evolution	Ischaemia-reperfusion injury	14 (19)
	(ALT > 1000 IU, Quick < 60%)
	Biliary complication	7 (9.5)
	Postoperative arterial complication	2 (2.7)
Median time from event to conversion		1 mo (r: 0.1-19)
Median time from LT to conversion		6 mo (r: 0.1-192)
Early/late conversion	< 1 yr/≥ 1 yr	42 (56.8)/32 (43.2)
Mean follow-up post-conversion		22 ± 19 mo (r: 0.5-74)
Median follow-up post-conversion		17.5 mo

HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HBV: Hepatitis B virus; ETOH: Cirrhosis due to alcohol; HIV: Human immunodeficiency virus; UNOS: United Network for Organ Sharing classification; ICU: Intensive care unit; LT: Liver transplantation; CET: Cranioencephalic trauma; CVA: Cerebrovascular accident; E-E: End-to-end choledoco-choledostomy; E-E + K: End-to-end choledoco-choledostomy + kehr; C-Y: Choledoco-jejunostomy; RBC: Red blood cells; IU: International units; r: Range.

Table 2 Causes of conversion and other comorbidities at the time of conversion to everolimus in 74 liver transplant patients n (%)

Cause of conversion
Refractory rejection	23 (31.1)	Resolution	17 (73.9)
Extended HCC in explanted liver	14 (19)	Prevention of recurrence	7 (50)
HCC recurrence during follow-up	6 (8.1)	Stabilization	0 (0)
De novo tumour	13 (17.6)	Prevention of recurrence	8 (61.5)
CNI-related neurotoxicity	8 (10.8)	Resolution or Stabilization	8 (100)
Renal dysfunction	6 (8.1)	Resolution or Amelioration	3 (50)
Other causes	4 (5.4)	Resolution	2 (50)
Comorbidity at time of conversion
Chronic renal insufficiency	22 (29.8)	Resolution or Amelioration	15 (68.2)
Diabetes mellitus	21 (28.4)	Resolution or Amelioration	8 (38)
Arterial hypertension	25 (33.8)	Resolution or Amelioration	3 (12)
Dyslipidemia	30 (40.5)	Resolution or Amelioration	2 (6.7)

Outcome to everolimus shown as resolution, stabilization or amelioration of the cause or comorbidity. In 45 of 74 patients (60.8%), the cause was resolved, stabilized or ameliorated. HCC: Hepatocellular carcinoma; CNI: Calcineurin inhibitors. Other causes include: 1 chronic biliary cirrhosis recurrence plus chronic rejection, 1 sinusoidal hepatic fibrosis, 1 graft-versus-host disease, 1 chronic cholostatic liver dysfunction in the postoperative period.

Table 3 Type of immunosuppression pre- and post-conversion to everolimus

Pre-conversion	n = 74	Post-conversion	n = 74
FK + MMF + ST	16	FK + EVER	38
FK + MMF	20	FK + EVER + MMF	1
FK + ST	12	FK + EVER + ST	11
FK	21	FK + EVER + MMF + ST	4
CyA + MMF + ST	1	CyA + EVER	3
CyA + MMF	1
CyA	2	EVER	2
		EVER + ST	5
MMF + ST	1	EVER + MMF	2
		EVER + MMF + ST	8

FK: Tacrolimus; MMF: Mycophenolate mofetil; ST: Steroids; CyA: Neoral cyclosporine; EVER: Everolimus.

Table 4 Comparison between patients with hepatocellular carcinoma outside Milan criteria in the explanted liver receiving everolimus and a historical cohort not receiving mTOR inhibitors, and liver-transplanted patients with recurrence of hepatocellular carcinoma receiving everolimus and a historical cohort not receiving mammalian target of rapamycin inhibitors n (%)

HCC outside Milan criteria inexplanted livers	Patients receiving everolimusn = 14	Historical controls without mTORin = 14	P
Recipient age at transplant (yr)	55.5 ± 11.3	56.38 ± 7.1	NS
Recipient sex (male-female) (%)	86-14	79 - 21	NS
Child–Pugh status	6.7 ± 1.8	6.5 ± 1.4	NS
MELD score	13.6 ± 5	11.4 ± 3.4	NS
Size of largest tumour on pathologic exam	3.43 ± 1.50	3.152 ± 1.05	NS
Nº of tumours at pathologic exam	2.70 ± 1.7	2.74 ± 1.7	NS
Microvascular invasion	10 (78)	4 (29)	0.02
Macrovascular invasion	5 (39)	0	0.01
Satellitosis	7 (50)	3 (21.4)	NS
Well-moderately differentiated tumour (%)	31-69	50-50	NS
Mean alpha-fetoprotein	366 ± 771	55 ± 125	NS
Median alpha-fetoprotein	12 (3-2571)	8 (2-445)	NS
HCC treatment while on waiting list	9 (64.3)	8 (57)	NS
Mean donor age in years	59 ± 14.9	58 ± 12.6	NS
Mean and median patient survival post-LT (mo)	56 ± 8.5 (59)	67 ± 11 (54)	NS
HCC recurrence in post-LT follow-up	n = 6	n = 6	P
Recipient age at transplant (yr)	53.6 ± 10	46.5 ± 13	NS
Recipient sex (male-female) (%)	100-0	83-17	NS
Milan criteria in explanted liver (yes-no) (%)	33-67	33-67	NS
Mean donor age (yr)	52.1 ± 16	41 ± 12.8	NS
Months from LT to recurrence	37.9 ± 45	28.5 ± 30	NS
Immunosuppression at recurrence (CyA-FK) (%)	17-83	17-83	NS
Type of recurrence (intra–extrahepatic) (%)	17-83	17-83	NS

HCC: Hepatocellular carcinoma; mTORi: Mammalian target of rapamycin inhibitors; LT: Liver transplantation; CyA: Neoral cyclosporine; FK: Tacrolimus; NS: No significant.

Table 5 Comparison between liver-transplanted patients with de novo tumour receiving everolimus and a historical cohort not receiving mammalian target of rapamycin inhibitors

	Patients receiving everolimusn =13	Historical controls without mTORin = 13	P
Recipient age at transplant (yr)	60.8 ± 5.8	59.5 ± 6.6	NS
Recipient sex (male-female) (%)	77-23	75-25	NS
Indication for LT (%)			NS
Postnecrotic-HCC in cirrhosis	68%	70%	NS
Mean time from LT to diagnosis of de novo tumour (mo)	67 ± 50	65.9 ± 37	NS
Tumour site and histology			NS
Colon ADK	4	4
Prostate ADK	2	2
Lung SCC	1	1
Larynx SCC (4)	2	2
Esophagus SCC(3) + ADK(1)	2	2
Anus SCC	1	1
Breast IDC	1	1
Type of treatment			NS
Surgery ± QT ± RT	10	10
QT ± RT	3	3	NS
Immunosuppression at diagnosis
Cyclosporine-tacrolimus (%)	8-92	24-76	NS
Mean patient survival from diagnosis of tumour (mo)	32.9 ± 15	30.7 ± 20.6	NS

mTORi: Mammalian target of rapamycin inhibitors; LT: Liver transplantation; HCC: Hepatocellular carcinoma; ADK: Adenocarcinoma; SCC: Squamous cell carcinoma; IDC: Infiltrative ductal carcinoma; QT: Chemotherapy; RT: Radiotherapy; NS: No significant.

Table 6 Efficacy in cases of early (within one year post-transplantation) and late (after one year post-transplantation) conversion to everolimus n (%)

Early conversion
Cause of conversion	42 (56.8)	Resolution/stabilization or prevention of recurrence in 29 patients (69)
Refractory rejection	13 (17.6)	Resolution in 11 (84.6)
Advanced HCC in explanted liver	12 (16.3)	Prevention of recurrence in 6 (50)
HCC recurrence during follow-up	3 (4.1)	-
De novo tumour	0	-
CNI-related neurotoxicity	8 (10.8)	Resolution or amelioration in 8 (100)
Renal dysfunction	4 (5.4)	Resolution in 3 (75)
Other causes	2 (2.6)	Resolution in 1 (50)
Late conversion
Cause of conversion	32 (43.2)	Resolution/stabilization or prevention of recurrence in 16 patients (50)
Refractory rejection	10 (13.5)	Resolution in 6 (60)
Advanced HCC in ex planted liver	2 (2.7)	Prevention of recurrence in 1 (50)
HCC recurrence during follow-up	3 (4.1)	-
De novo tumour	13 (17.6)	Prevention of recurrence in 8 (61.5)
CNI-related neurotoxicity	0	-
Renal dysfunction	2 (2.7)	Resolution in none (0)
Other causes	2 (2.7)	Resolution in 1 (50)

HCC: Hepatocellular carcinoma; CNI: Calcineurine inhibitors.

Table 7 Adverse events, causes of discontinuation and mortality n (%)

	Patients receiving everolimus (n = 74)
Adverse events	27 (36.5)
Dyslipidemia	27 (36.5)
Infections	9 (12.2)
Mucositis	3 (4.1)
Diarrhoea	1 (1.4)
Proteinuria	1 (1.4)
Acute rejections post-conversion	11 (14.9)
Causes of discontinuation	21 (28.4)
Resolution of the cause of conversion	6 ( 8.1)
Non-responding rejection and retransplantation	6 ( 8.1)
Drug-related adverse events	5 ( 6.7)
Intercurrent surgery	4 ( 5.5 )
Causes of mortality	25 (33)
HCC recurrence during follow-up	10
De novo tumour	4
HCV recurrence	4
Chronic rejection	4
Sepsis	1
Graft-vs-host disease	1
Other causes	1

HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus.

Table 8 Future challenges in liver transplantation and the potential role of everolimus

Future challenges	Potential role of everolimus
More marginal donors	Renal function protection
Recipients with more serious disease, selected by MELD	Renal function protection
Recipients with more serious disease, with metabolic syndrome	Prevention of cardiovascular events
Less HCV cirrhosis but more aggressive strains	Antifibrotic effect
More NASH	Prevention of cardiovascular events
More metabolic syndrome during follow-up	Prevention of cardiovascular events
More HCC recurrence	Antiproliferative effect
More de novo tumours	Antiproliferative effect
CNIe-related neurotoxicity	Good neurological profile

MELD: Model for end-stage liver disease; HCV: Hepatitis C virus; NASH: Non-alcoholic steato hepatitis; HCC: Hepatocellular carcinoma; CNI: Calcineurine inhibitors.